chr19-50402053-G-A

Position:

chr19-50402053-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002691.4(POLD1):c.518G>A(p.Ser173Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00539 in 1,614,076 control chromosomes in the GnomAD database, including 416 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 212 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 204 hom. )

Consequence

POLD1
NM_002691.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.63

Variant links:

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019380748).

BP6

Variant 19-50402053-G-A is Benign according to our data. Variant chr19-50402053-G-A is described in ClinVar as [Benign]. Clinvar id is 380634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50402053-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4 linkuse as main transcript	c.518G>A	p.Ser173Asn	missense_variant	5/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 linkuse as main transcript	c.518G>A	p.Ser173Asn	missense_variant	5/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes

AF:

0.0291

AC:

4435

AN:

152152

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.00770

AC:

1934

AN:

251044

Hom.:

AF XY:

0.00540

AC XY:

733

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00657

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00291

AC:

4249

AN:

1461806

Hom.:

204

Cov.:

AF XY:

0.00245

AC XY:

1781

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.101

Gnomad4 AMR exome

AF:

0.00722

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.00659

GnomAD4 genome

AF:

0.0292

AC:

4452

AN:

152270

Hom.:

212

Cov.:

AF XY:

0.0281

AC XY:

2090

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.101

Gnomad4 AMR

AF:

0.0129

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.00605

Hom.:

Bravo

AF:

0.0340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0958

AC:

422

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00925

AC:

1123

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 18, 2016	Variant summary: The POLD1 c.518G>A (p.Ser173Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 1114/120932 control chromosomes (including 57 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1000194 (1030/10298). This frequency is about 7041 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is a common benign polymorphism found primarily in the populations of African. Taken together, this variant is classified as Benign. -

Colorectal cancer, susceptibility to, 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 25, 2017	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLD1 p.Ser173Asn variant was identified in dbSNP (ID: rs1726803) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 2724 (141 homozygous) of 276964 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2439 (139 homozygous) of 23962 chromosomes (freq: 0.10), Other in 20 of 6462 chromosomes (freq: 0.003), Latino in 231 (2 homozygous) of 34410 chromosomes (freq: 0.007), European Non-Finnish in 31 of 126566 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10142 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.00007), while not observed in the East Asian and European Finnish populations. The p.Ser173 residue is conserved in in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact of Asn to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.14

T;.;.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.71

.;.;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.;.;.;N

MutationTaster

Benign

0.99

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.0

N;.;.;.;.

REVEL

Benign

0.097

Sift

Benign

0.57

T;.;.;.;.

Sift4G

Benign

0.49

T;T;D;T;T

Polyphen

0.45

B;.;.;.;B

Vest4

0.20

MVP

0.54

MPC

0.29

ClinPred

0.033

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.067

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over